The brain is generally considered immunoprivileged, although increasing examples of immunological responses to brain antigens, neuronal expression of Major Histocompatibility Class I genes and neurological autoimmunity have been recognized. In this application we propose the use of vaccination strategies to generate autoantibodies which target a specific brain protein, the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor. We present preliminary data to show the development of a novel vaccine, the peroral administration of AAV vectors targeting the lamina propria resulting in stable transgene expression in a variety of cells including professional antigen presenting cells (APC). This viral vaccine is associated with a humoral response to the transgene, both foreign and self-antigens, resulting in circulating autoantibodies in this latter case. Moreover, we show that the administration of NMDAR1-expressing vectors, but not control vectors, is associated with anti-epileptic and neuroprotective activity in experimental animal models. In this grant application we propose to extend these preliminary studies to further define the mechanism of action of this self-antigen immunization and to determine whether such a vaccination strategy targeting brain proteins is feasible and may have therapeutic potential for neurological disorders. The proposal is now focused on testing the hypothesis that the neuroprotective phenotype we observe is mediated via antibodies. Secondly, we will explore the mechanism of the vaccination, see if the observation is generalizable to other cell surface receptors, and also compare this approach with other more traditional protein vaccination strategies. It includes the use of adoptive transfer methods to definitively test the hypothesis of an antibody mediated mechanism as well as the use of CD4 and CD8 knockout mice to help dissect out which components of the immune system mediated the phenotypic effects. It characterizes and further defines the mechanism of action of the vaccination using electrophysiological and calcium imaging studies on primary neurons and it also involves testing a variety of approaches in an established model of neurological disease. The successful completion of these experiments is likely to represent a significant advance in te development of a novel therapeutic approach for neurological disorders.